1-heteruarylazetidines and -pyrrolidines, process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to new 1-heteroarylazetidines and new 1-heteroarylpyrrolidines endowed with 5-HT 3  agonist activity of formula (I): ##STR1## in which A is --CH═N-- or --N═CH--; R is hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, cyano, carboxamido, trifluoromethyl, a vinyl group, a formyl group, a carboxyl group in free, salt or esterified form, hydroxyl, hydroxymethyl, mercapto, amine, mono- or di-(C 1-4  alkyl)amino, aminomethyl, mono- or di(C 1-4  alkyl)aminomethyl, 1-piperido, 1-pyrrolidino, 1-piperazino or 4-(C 1-4  alkyl)-1-piperazino, where R may replace any one of the hydrogen atoms of the heteroaryl nucleus; 
     R 1  is hydrogen or a methyl group; 
     R 2  and R 3 , which are identical or different, are hydrogen or C 1-4  alkyl; 
     n is 1 or 2; m is 0 or 1; and m+n≧2; 
     and addition salts with inorganic or organic acids of the compounds of formula (I). The invention also relates to pharmaceutical compositions containing these compounds, as well as to methods of treatment or prophylaxis of disorders which involve the peripheral or central serotoninergic systems.

This application is a Division of application Ser. No. 08/368,915, filedJan. 5, 1995 (pending), which is a Divisional of application Ser. No.08/127,038, filed Sep. 24, 1993, now U.S. Pat. No. 5,410,057.

The present invention relates to new 1heteroaryl azetidine andpyrrolidine derivatives endowed with agonist activity to the 5-HT₃receptors.

The invention also relates to the process for the preparation of thesecompounds, the new intermediates obtained by this process, theapplication of the said new compounds as drugs and the pharmaceuticalcompositions containing them.

Pyrazine, pyrimidine and pyridazine derivatives which can be substitutedinter alia by a 2- or 3-azetidinyl radical have been described inEuropean Patent Application EP-A-327155 as stimulants of centralmuscarine receptors.

Quinolines and naphthyridines substituted by a 1-azetidinyl radical,which are useful as bactericides, have been described in European PatentApplications EP-A-106489 and EP-A-153163.

Azetidine derivatives substituted by a heterocyclic ring on the nitrogenatom and by a substituted amino group in position 3 have been claimed inGerman Patent Application DE-A-2241097, where they are described asanalgesics and antiinflammatory agents.

European Patent EP-155870 mentions the use of 3-aminoazetidine, which isclaimed in the preparation of 3-amino-1-(6-chloropyrid-2-yl)azetidineendowed with anorexigenic activity.

3-Pyridinecarboxylic acid derivatives substituted by a fluorophenylaminogroup in position 2, by a fluorine atom in position 5 and inter alia byan optionally protected 3-aminopyrrolidino group in position 6 areclaimed as intermediates for the synthesis of bactericidal1,8-naphthyridines in patent BE-904086.

Japanese Patent Application JP 62033176 (WPI 87-082820) describes3-nicotinoylacetic acid derivatives substituted by a chlorine atom inposition 2, by a fluorine atom in position 5 and by, inter alia, anoptionally substituted cyclic amino group in position 6, asintermediates to naphthyridines, while derivatives of2-pyridylaminomethylenepropanedioic acid, also useful as intermediatesto naphthyridines, are described in EP-376870.

Finally, 3-amino-5-phenyl-1-(2-pyridyl)pyrrolidine, a possibleintermediate to histamine antagonists, as well as its stereoselectivesynthesis, have been described in J. Heterocycl. Chem., 1973, 10 (5),747-753.

It has now been found that certain 1-heteroarylazetidine and-pyrrolidine derivatives in which the nitrogen atom is bonded to anoptionally substituted pyridine, pyrazine or pyrimidine and the carbonin position 3 carries an aminomethyl or optionally alkylated amino grouphave a highly advantageous novel biochemical activity, showingthemselves to be selective agonists for the serotonin 5-HT₃ receptors.

More particularly, therefore, as first subject, the present inventionrefers to the new 1-heteroarylazetidines or pyrrolidines correspondingto the following formula (I) ##STR2## in which A demotes a --CH═CH--,--CH═N--or --N═CH--group;

R denotes a hydrogen atom, a halogen atom, a C₁ -C₄ alkyl, C₁ -C₄ alkoxyor C₁ -C₄ alkylthio group, a cyano, carboxamido, trifluoromethyl, vinylor formyl group, a carboxyl group in free, salt or esterified form, ahydroxyl, hydroxymethyl or mercapto group or an amino, mono- or di(C₁-C₄ alkyl)amino, aminomethyl, mono- or di(C₁ -C₄ alkyl)aminomethyl,1-piperidino, 1-pyrrolidino, 1-piperazino or 4-(C₁ -C₄alkyl)-1-piperazino group, it being possible for this group R to replaceany one of the hydrogen atoms of the heteroaryl nucleus;

R₁ is a hydrogen atom or a methyl group;

R₂ and R3, which are identical or different, denote a hydrogen atom or aC₁ -C₄ alkyl group;

n is 1 or 2,

m is 0 or 1 and m+n≧2

it being possible for the said compounds to be in any of the optionallypossible isomeric, racemic, enantiomeric and diastereoisomeric forms,and in the form of addition salts with inorganic or organic acids.

The compounds of formula (I) as defined above and their addition saltswith pharmaceutically acceptable acids exhibit advantageouspharmacological properties. More particularly, these products areendowed with selective agonist properties for the serotonin 5-HT₃receptors. These properties justify their application in therapeuticsfor the preparation of medications intended for the prophylaxis and forthe treatment of disorders of the serotoninergic system when it isdesired to have a selective agonist action mediated by the 5-HT₃receptors.

In the products of formula (I) and in what follows:

the term "C₁ -C₄ alkyl" denotes a linear or branched alkyl radicalcontaining from 1 to 4 carbon atoms, preferably methyl, ethyl, n-propyland isopropyl radicals, but also n-butyl, isobutyl, sec-butyl andtert-butyl radicals;

the term "C₁ -C₄ alkoxy" denotes an alkoxy radical with a straight orbranched chain containing from 1 to 4 carbon atoms, preferably methoxyand ethoxy radicals, but also propoxy, isopropoxy and linear, secondaryor tertiary butoxy radicals;

the term "C₁ -C₄ alkylthio" denotes an alkylthio radical with a linearor branched chain containing from 1 to 4 carbon atoms and preferablymethylthio, ethylthio and isopropylthio radicals;

the term "halogen atom" preferably denotes the chlorine or bromine atombut may also represent a fluorine or iodine atom;

the term "esterified carboxyl" preferably denotes a lower alkoxycarbonylgroup such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl,or a benzyloxycarbonyl group, whereas the term "carboxyl in salt form"preferably denotes a carboxyl group converted into salt with aninorganic base such as, for example, one equivalent of sodium,potassium, calcium, magnesium or ammonium, or an organic base such as,for example, methylamine, propylamine, trimethylamine,N,N-dimethylethanolamine, tri(hydroxymethyl)aminomethane, pyridine,picoline, dicyclohexylamine, benzylamine, procaine, lysine, arginine,N-methylglucamine or a compound of formula (I).

The addition salts of the compounds of formula (I) with inorganic ororganic acids may be, for example, the salts formed with hydrochloric,hydrobromic, hydriodic, nitric, sulphuric, oxalic, phosphoric,propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric,citric, oxalic, glyoxylic, aspartic and ascorbic acids, sulphonic acidssuch as methanesulphonic, ethanesulphonic, methanedisulphonic andbenzenesulphonic acid and the like. Salts formed with hydrochloric acidare preferred in particular.

A preferred class of compounds of formula (I) comprises the compounds offormula (Ia) which corresponds to the formula (I) where n and m are 1##STR3## and R, A, R₁, R₂ and R₃ are as defined above.

A particularly preferred group of compounds of formula (Ia) according tothe present invention comprises the compounds of formula (Ia) in which Adenotes a --CH═CH-- (pyridine derivatives) or --N═CH-- (pyrazinederivatives) group, R, R₂ and R₃ are as defined above and R₁ ishydrogen, and their addition salts with acids.

Still more preferred are the compounds of formula (Ia) in which A, R₁,R₂ and R₃ are as defined above in the definition of a preferred groupand R denotes a hydrogen or halogen atom, a C₁ -C₄ alkyl, C₁ -C₄ alkoxy,cyano, carboxamido, trifluoromethyl, vinyl or formyl group or carboxylin free, salt or esterified form, or an amino group, and their additionsalts with acids.

Particularly preferred are the compounds of formula (Ia) in which Adenotes a --CH═CH-- group, R denotes a chlorine or bromine atom inpositions 3, 5 or 6, R₁ is a hydrogen atom and R₂ and R₃ are identicaland denote a hydrogen atom or a C₁ -C₄ alkyl group, and their additionsalts with acids.

Another particular class of compounds of formula (I) comprises thecompounds of formula (Ib) which corresponds to the formula (I) where nis 2 ##STR4## m is 0 or 1 and all the other substituents R, A, R₁, R₂and R₃ are as defined above.

A particularly preferred group of compounds of formula (Ib) according tothe present invention comprises the compounds of formula (Ib) in which Adenotes a --CH═CH-- (pyridine derivatives) or --N═CH-- (pyrazinederivatives) group, m, R, R₂ and R₃ are as defined above and R₁ ishydrogen, and their addition salts with acids.

Still more preferred are the compounds of formula (Ib) in which m, A,R₁, R₂ and R₃ are as defined above in the definition of a preferredgroup, and R denotes a hydrogen or halogen atom, a C₁ -C₄ alkyl, C₁ -C₄alkoxy, cyano, carboxamido, trifluoromethyl, vinyl, formyl, carboxyl infree, salt or esterified form or an amino group, and their additionsalts with acids.

Particularly preferred are the compounds of formula (Ib) in which Adenotes a --CH═CH-- group, R denotes a chlorine or bromine atom inpositions 3, 5 or 6, m is 0, R₁ is a hydrogen atom and R₂ and R₃ areidentical and denote a hydrogen atom or a C₁ -C₄ alkyl group, and theiraddition salts with acids.

The compounds of formula (I) of the present invention can be preparedfrom a heterocyclic compound of formula (II) ##STR5## in which A has themeaning given above, Hal denotes a halogen atom, chlorine, bromine andiodine being preferred, and R' corresponds to R or to an R groupprotected by an easily removable suitable protective group; and from anazetidine or pyrrolidine derivative of formula (III): ##STR6## in whichn, m and R₁ are as defined above and P denotes a temporary protectivegroup for the amino group which is suitably chosen.

The starting compounds of formula (II) are generally products which areavailable commercially or which can be prepared in the laboratory byvery simple reactions which are well known to a person skilled in theart.

The starting compounds of formula (III) where n is 1 can be preparedfrom 1-benzhydrylazetidin-3-ol or 1-benzhydryl-3-methylazetidin-3-ol byconversion of the hydroxyl group into a mesyloxy group, replacement ofthe latter with a cyano group, reduction of the cyano group toaminomethyl, protection of the amino group with a suitable group P andselective removal of the benzhydryl group by catalytic hydrogenation.The starting pyrrolidines of formula (III) where n is 2 and m is 0 canbe prepared from 1-benzyl-3-pyrrolidone (J. Org. Chem., 1965, 30, 740).When R₁ is a hydrogen atom, 1-benzyl-3-pyrrolidone is converted into thecorresponding oxime by reaction with hydroxylamine. The oxime functionalgroup is then reduced with the aid of a mixed hydride such as LiAlH₄,the primary amino group which is formed is protected by introducing theprotective group P and the 1-benzyl group is removed by catalytichydrogenation with platinum or palladium catalysts.

When R₁ denotes a methyl group,1-benzyl-3-methyl-3-acetylaminopyrrolidine can be obtained by followingthe method described in EP-132845 (Example 7) and, optionally, beforeremoving the benzyl group by catalytic hydrogenation, by removing theacetyl group by hydrolysis and by introducing a different protectivegroup P.

The compounds of formula (III) where n is 2 and m is 1 are easilyprepared from 1-benzyl-3-pyrrolidinol, which is a commercial product,and from 1-benzyl-3-methyl-3-pyrrolidinol (EP-132845-Example 7) byconversion into the corresponding mesyl derivative, replacement of themesyloxy group with a cyano group and reduction of the cyano group toaminomethyl with the aid of LiAlH₄ finally followed by deprotection bycatalytic hydrogenation with platinum catalysts.

The reaction between the compound of formula (II) and the derivative offormula (III) produces an intermediate compound of formula (IV) ##STR7##in which n, m, R', A, R₁ and P are as defined above, and the successiveremoval of the protective group(s) produces the compound of formula (X)where n, m, R, and R₁ are as defined above and R₂ and R3 are twohydrogen atoms. When it is intended to obtain a compound of formula (I)where R₂ and/or R3 are other than hydrogen, this is followed by themono- or dialkylation of the amino group using known conventionalmethods.

Under preferred conditions of implementation of the invention the aboveprocess is carried out as follows.

The reaction of the compound of formula (II) with the compound offormula (III) is conducted in an organic solvent such as an alcohol,preferably n-butanol, n-pentanol or n-hexanol, in dimethylformamide,dimethyl sulphoxide, sulpholane, acetonitrile, pyridine and similarsolvents, at a temperature which is generally between 50° C. and 200°C., in the presence of an alkaline condensing agent such as an alkalimetal hydroxide, carbonate or bicarbonate or of a tertiary amine. After20 to 120 hours the reaction is complete and the intermediate compoundof formula (IV) thus obtained is isolated by the usual techniques.

The protective group(s) is (are) then removed in the usual conditionswhich are known to a person skilled in the art and which depend on theprotective group chosen.

The preferred protective groups for the amino functional group aret-alkoxycarbonyl groups such as t-butoxycarbonyl (BOC) ort-amyloxycarbonyl (AOC), the BOC group being particularly preferred. Theremoval of these groups is therefore easily performed by acidichydrolysis using methods which are well known in the literature andespecially by the action of trifluoroacetic acid or of hydrochloric acidin an alcoholic solvent.

A protective group for the amino functional group which may also beemployed is the acetyl group, which can be removed using well-knownacidic or basic hydrolysis techniques, for example by heating theblocked intermediate of formula (IV) in an aqueous solution of aninorganic or organic acid, preferably hydrochloric acid, or by treatingit with an inorganic base, preferably sodium hydroxide.

The various reactive functional groups which are optionally present insome starting compounds of formula (II) can be protected, if necessaryor appropriate; these are, for example, hydroxyl, amino, carboxyl andmercapto groups, which can be protected conventionally. As an example ofprotection for the hydroxyl group there may be mentioned,nonexhaustively, silyl radicals such as trimethylsilyl andt-butyldimethylsilyl and etherifying groups such as thetetrahydropyranyl group.

The amino substituent of the heterocyclic nucleus can be protected, asindicated above, with a t-alkoxycarbonyl group.

The carboxyl group can be protected in the form of an easily splittableester such as a benzyl or t-butyl ester or of esters which are known inpeptide chemistry. It can also be protected in the form of acorresponding protected alcohol and then regenerated by oxidation.

Finally, the mercapto group can be protected by forming a mixed orsymmetrical disulphide.

Other protective groups which are appropriate in the envisaged reactionconditions and methods for removing them at the end of the reaction aredescribed in the literature (see, for example, D. Barton and W.C. Ollis,Comprehensive Organic Chemistry, vol. 5, pp. 323-331 and the referencesto be found mentioned therein) and are well known to a person skilled inthe art, who is therefore capable of choosing the most appropriate onesdepending on the circumstances.

A compound of formula (I) is thus obtained in which R₂ and R₃ are bothhydrogen. This compound can therefore be isolated and/or converted intoone of its addition salts by treatment with a hydroalcoholic or organicsolution of the acid forming the salt.

If it is intended to obtain a compound of formula (I) in which one of R₂and R₃ denotes an alkyl group, the primary amine thus obtained iscondensed with the appropriately chosen aldehyde or ketone by forming anintermediate Schiff base, which is reduced using hydrides which are wellknown to a person skilled in the art, typically sodium cyanoborohydride.

This secondary amino group can then be subsequently alkylated byconventional methods for alkylating amino groups, for example byreaction with an alkyl halide, preferably an alkyl iodide. Dialkylderivatives where R₂ and R₃ differ from each other can thus be obtained.

When it is intended to obtain a compound of formula (I) where R₂ and R₃are identical and denote an alkyl group, the conventional method isfollowed directly using at least the stoichiometric quantity ofalkylating agent.

The compounds of formula (Ib) of the present invention contain at leastone chiral carbon atom, that carrying the (CH₂)_(m) --NR₂ R₃ group, andexist, therefore, in the form of racemates or enantiomers.

The pure enantiomers can be obtained either by starting with a compoundof formula (III) in optically active form or by resolving the racemicmixture of the compound (Ib), for example by means of a resolving agentsuch as a derivative of tartaric acid or of other optically activeacids.

The starting compounds of formula (III), in their turn, can be obtainedin an optically active form by resolving the racemates usingconventional methods which are known to a person skilled in the art,such as, for example, the formation of diastereoisomeric salts withoptically active acids or the use of chiral chromatography columns.

If the substituents R, R₂ and R₃ contain additional chiral atoms then anumber of isomeric forms are possible and the compounds (Ib) could be inthe form of racemates, enantiomers or diastereoisomers, all of whichisomeric forms are included within the subject matter of the presentinvention.

The possible optically active forms of the products of formula (Ia)which exist when R₁ is a methyl group and/or the substituents R, R₂ andR₃ contain chiral atoms, can be prepared by resolving the racemates bythe usual methods known to a person skilled in the art, such as, forexample, the formation of diastereoisomeric salts or the use of chiralchromatography columns.

As an alternative to the general method described above or, preferably,when the starting compound of formula (II) is not a product that isavailable commercially or easily prepared, some compounds of formula (I)can be obtained by modifying the group R in other compounds (I) or intheir intermediates (IV) using reactions which are well known inconventional chemistry.

For example, when it is intended to obtain a compound of formula (I)where R is a vinyl group, it is possible to start with a compound (II)where R is a halogen atom, thus to obtain an intermediate compound (IV)where R is a halogen atom and then to replace this atom with a vinylgroup, for example by reaction with a tin vinyl derivative such astributylvinyltin, in the presence oftetrakis(triphenylphosphine)palladium. The nitrogen atom of the aminogroup can then be deblocked and optionally alkylated thus to obtaincompounds (I) where A, R₁, R₂ and R₃ are as defined above and R is avinyl group. Alternatively, before deblocking the amino group, the vinylgroup can be oxidized with, for example, an alkali metal periodate inthe presence of osmium tetraoxide as catalyst and to obtain thecorresponding compounds where R is a formyl group.

In their turn, these latter compounds can be oxidized, for example withthe Jones reactant, which is made up of a solution of chromic anhydridein sulphuric acid, or with alkali metal chlorite, giving thecorresponding carboxylic acids. Esterification of the latter, forexample with the corresponding alcohol in the presence of a dehydratingagent, produces the desired esters.

Similarly, the esterified carboxyl radical can be reduced to ahydroxymethyl radical in the usual conditions which are known to aperson skilled in the art, such as especially by the action of lithiumaluminium hydride, diisobutylaluminium hydride or other reducing agentswhich are known to a person skilled in the art.

The optional methoxy substituent of the products described above can, ifdesired, be converted into a hydroxyl group, for example with borontribromide in an inert organic solvent such as, for example, methylenechloride.

A halogen atom on the heteroaromatic nucleus can also be replaced with asubstituted amino radical, for example by treating the halogen compoundwith a secondary amine such as dialkylamines or cyclic amines, atambient temperature in a solvent such as an alcohol, especially ethanolor methanol.

Similarly, a halogen atom on the heteroaromatic nucleus can be convertedinto an alkoxy, e.g. methoxy, group by reaction with a nucleophile suchas alkoxide, e.g. methoxide.

Similarly, this halogen atom can be converted into a cyano group byreaction, for example, with tributylcyanotin in the presence oftetrakis(triphenylphosphine)palladium. Partial hydration of compounds(I) or (IV) where R is a cyano group gives the corresponding compoundswhere R is a carboxamido group. This hydrolysis of the cyano group to acarboxamido group can be conducted under controlled acidic catalysisconditions or, more appropriately, under mild basic conditions in thepresence of hydrogen peroxide as catalyst.

From the intermediate compounds of formula (IV) where R is a cyano orcarboxamido group it is then possible to obtain the correspondingcompounds where R is an aminomethyl group by reduction with a mixedhydride such as, for example, lithium aluminium hydride and itsalkoxylated derivatives.

The amino group can then be mono- or dialkylated by the methodsdescribed above.

Other reactions, which are well-known in conventional chemistry, can beemployed to convert one substituent R into another, either in the finalproducts (I) or in the protected intermediates (IV); all methods forpreparing the compounds (I) involving these reactions are thereforeincluded within the concept of the present invention.

A subsequent subject of the present invention is therefore a process forthe preparation of a compound of formula (I) ##STR8## in which A denotesa --CH═CH--, --CH═N-- or --N═CH-- group;

R denotes a hydrogen atom, a halogen atom, a C₁ -C₄ alkyl, C₁ -C₄ alkoxyor C₁ -C₄ alkylthio group, a cyano, carboxamido, trifluoromethyl, vinylor formyl group, a carboxyl group in free, salt or esterified form, ahydroxyl, hydroxymethyl or mercapto group, an amino, mono- or di(C₁ -C₄alkyl)amino, aminomethyl, mono- or di(C₁ -C₄ alkyl)aminomethyl,1-piperidino, 1-pyrrolidino, 1-piperazino or 4-(C₁ -C₄alkyl)-1-piperazino group, it being possible for this group R tosubstitute any one of the hydrogen atoms of the heteroaryl nucleus;

R₁ is a hydrogen atom or a methyl group;

R₂ and R3, which are identical or different, denote a hydrogen atom or aC₁ -C₄ alkyl group;

n is 1 or 2; m is 0 or 1 and n+m≧2 characterized in that ahalosubstituted heterocyclic compound of formula (II) ##STR9## in whichA has the meaning given above, R' corresponds to R or to a group Rprotected by an easily removable appropriate protective group and Haldenotes a halogen atom, is reacted with an azetidine or pyrrolidine offormula (III) ##STR10## in which n, m and R₁ are as defined above and Pis a temporary protective group for the amino group which is suitablychosen, to obtain an intermediate compound of formula (IV) ##STR11## inwhich n, m, R', A, R₁ and P are as defined above, the protective groupspresent are next removed thus to obtain a compound of formula (I) wheren, m, A, R and R₁ are as defined above and R₂ and R₃ are hydrogen, and

when it is intended to obtain a compound of formula (I) in which R₂and/or R₃ are other than hydrogen, the nitrogen atom is alkylated usingsuitable methods; and

the final product is optionally converted into one of its addition saltswith inorganic or organic acids; and

optionally after each stage a substituent R may be converted intoanother one by reactions which are known per se.

The compounds of formula (IV) where n, m, R', A, R₁ and P are as definedabove are new industrial products and intermediates necessary for thepreparation of the compounds of formula (I) and therefore represent aspecific further subject of the present invention.

The compounds of formula (I) as defined above and their addition saltswith pharmaceutically acceptable acids exhibit advantageouspharmacological properties.

These products are endowed with selective agonist properties for theserotonin 5-HT₃ receptor.

The affinity of the compounds of formula (I) for the 5-HT₃ receptors hasbeen demonstrated with the aid of in-vitro binding tests by employingthe 5-HT₃ binding sites present in the cerebral cortex of the rat (G.J.Kilpatrick, B.J. Jones and M.B. Tyers. Identification and distributionof 5-HT₃ receptors in rat brain using radioligand binding. Nature, 1987;330: 746-8) and, as labelled ligand, [³ H]-BRL 43694 (granisetron), apowerful and specific antagonist of the 5-HT₃ receptors.

The preparation of the membranes and the binding test were performedusing the method described by Nelson and Thomas (D.R. Nelson and D.R.Thomas. [³ H]-BRL 43694 (granisetron), a specific ligand for 5HT₃binding sites in rat brain cortical membranes. Blochem. Pharmacol.,1989; 38: 1693-5).

The results have been evaluated with the "Accufit saturation" nonlinearfitting methods in the case of the saturation studies (H.A. Feldman.Mathematical theory of complex ligand-binding systems at equilibrium:some methods of parameter fitting. Analyt. Blochem., 1972; 48: 317-38)and "Accufit competition" in the case of the displacement studies (H.A.Feldman, D. Rodbard and D. Levine. Mathematical theory of cross reactiveradioimmunoassay and ligandbinding systems at equilibria. Analyt.Blochem., 1972; 45: 530-56).

To obtain the affinities of the compounds a concentration of 0.5 nM of[3H]-BRL 43694 was employed in the competition studies.

In these in-vitro tests the compounds of formula (I) have shownthemselves to be generally very powerful in the displacement of [³H]-BRL 43694.

The affinity has been confirmed and the agonist activity in respect ofthe 5-HT₃ receptors has been demonstrated also by virtue of studies inthe anaesthetized rat, in particular by administering the compoundsintravenously and observing the fugitive decrease in the cardiacfrequency (Bezold-Jarisch effect) whose intensity varies according tothe dose.

This effect is inhibited by the selective antagonists for the 5-HT₃receptors (for example ICS 205930 and zacopride), whereas it is notinhibited by the antagonists for the D receptors of serotonin (forexample methysergide).

More particularly, the Bezold-Jarisch effect produced by the compoundsof formula (I) has been evaluated by employing Sprague-Dawley ratsbetween 200 and 300 g in weight, anaesthetized with an intraperitonealdose of 1.25 g/kg of urethane. The arterial pressure is recorded at acarotid artery and the cardiac frequency evaluated using the pulsefrequency with the aid of a cardiotachymeter. A catheter is placed inthe jugular vein for administering the substances.

Different doses of the compounds to be tested are administeredintravenously in a volume of 0.5 ml/kg.

The bradycardia caused by each dose is expressed as inhibition as apercentage of the basal frequency. It is thus possible to calculate theED₅₀, that is to say the dose which decreases the cardiac frequency by50% in the treated animals.

The most advantageous compounds have shown results, expressed as ED50,which are between 0.5 and 10 μg/kg.

These properties justify the application of new compounds of formula (I)according to the invention in therapeutics in the treatment of disorderswhich involve either the peripheral or the central serotoninergic systemwhen it is desired to have a selective agonist action mediated by the5-HT₃ receptors. It is possible, for example, to envisage thetherapeutic use of these products in the treatment of dysthimicdisorders, or else in cases of anxiety or of psychotic disorders.

The use of these products in the treatment of disorders of intestinalmotoricity can also be envisaged, in particular in the treatment ofconstipation.

A further subject of the invention therefore the use of the compounds offormula (I) where n, m, R, A, R₁, R₂ and R₃ have the meanings givenabove, and of their pharmaceutically acceptable salts, as drugs.

The invention extends to the pharmaceutical compositions containing, asactive principle, at least one of the compounds as defined above.

These pharmaceutical compositions can be administered orally, rectallyor parenterally.

These compositions can be solid or liquid and may take anypharmaceutical form commonly employed in human medicine such as, forexample, simple or sugarcoated tablets, gelatin capsules, granulates,solutions or suspensions for oral administration, suppositories andinjectable preparations; they are prepared by the usual methods. Theactive principle can be incorporated therein in excipients which areusually employed in these pharmaceutical compositions, such as talc, gumarabic, lactose, starch, magnesium stearate, cacao butter, aqueous ornonaqueous carriers, fatty substances of animal or vegetable origin,paraffinic derivatives, glycols, various wetting, dispersing oremulsifying agents, stabilizers and the like.

The usual posology, which can vary depending on the specific productemployed, the conditions and the weight of the subject being treated,the disorder in question and the method of administration, can besuitably between 1 and 1000 mg daily in an adult.

The following examples illustrate the invention without, however,limiting it.

PREPARATION I

a) A mixture of 50 g (0.157 mol) of 1-benzhydryl-3-mesyloxyazetidine (J.Org. Chem. 1972, 37, 3953-3955) and 23.5 g (0.479 mol) of sodium cyanidein 340 ml of dimethylformamide and 43 ml of water is heated to 60° C.for 5 hours. The reaction mixture is left at ambient temperatureovernight and is then poured into 2000 ml of water/ice. The solidproduct is recovered by filtration and is purified by being suspended in800 ml of water and being filtered. The product thus obtained is driedand crystallized from isopropyl ether to obtain 20 g of1-benzhydryl-3-azetidinecarbonitrile. M.p. 142°-146° C.

b) 0.37 g (0.008 mol) of lithium aluminium hydride in 40 ml of anhydrousethyl ether are stirred at ambient temperature and 1 g (0.004 mol) ofthe compound obtained in stage a) above is added to it portionwise over10 minutes. After refluxing for 2.5 hours the mixture is cooled anddiluted with water. The organic phase is separated off, washed withwater and dried. 3-Aminomethyl-1-benzhydrylazetidine (1.15 g)hydrochloride precipitates on addition of isopropanol saturated withhydrogen chloride. M.p. 202°-204° C.

c) A solution of 7.5 ml (0,073 mol) of acetic anhydride in 10 ml ofethyl acetate is added slowly to a mixture of 18 g (0.0713 mol) of3-aminomethyl-1-benzhydrylazetidine obtained from the correspondinghydrochloride of stage b) by neutralization with 10% sodium hydroxide,extraction with ethyl acetate and evaporation of the solvent, in 150 mlof ethyl acetate. The reaction mixture is stirred at ambient temperaturefor 1 h, is cooled and 50 ml of 2N NaOH are added to it with vigorousstirring. After 10 minutes stirring, the organic phase is separated off,is washed with water and is dried and concentrated at reduced pressureto obtain 20 g of 3-acetylaminomethyl-1benzhydrylazetidine. M.p.117°-119° C.

d) 19.5 g (0.0662 mol) of the compound obtained in stage c), 200 ml of95% ethanol, 3.91 g of 20% Pd(OH)₂ on carbon and 5.4 ml of concentratedhydrochloric acid are charged into a hydrogenation apparatus. They areplaced under a hydrogen atmosphere and hydrogenated at ambient pressure,at 40° C., for 3 hours. After filtering, the filtrate is concentrated byevaporation at reduced pressure and the oily residue is taken up withbenzene (2×50 ml) and then with acetone. The organic solvent isevaporated at reduced pressure to obtain 10 g of3-acetylaminomethylazetidine hydrochloride.

PREPARATION II

a) A solution of 31 g (0.0142 mol) of di-tert-butyl dicarbonate in 70 mlof anhydrous chloroform is added dropwise to a solution of 35.9 g (0,142mol) of 3-aminomethyl-1-benzhydrylazetidine in 360 ml of anhydrouschloroform under nitrogen atmosphere and is left stirred at ambienttemperature for 6 hours. The solvent is evaporated off and the oilyresidue is taken up with a small quantity of an ethyl ether/hexanemixture. The solid product thus obtained is filtered off and dried inthe oven to obtain 36.5 g of1-benzhydryl-3-tert-butoxycarbonylaminomethylazetidine. M.p. 108°-110°C.

b) A mixture of 36.5 (0.103 mol) of this compound and 10 g of 20%Pd(OH)₂ on carbon in 650 ml of absolute ethanol is heated to 50°-60° C.under a hydrogen atmosphere. After 4 hours, when the theoreticalquantity of hydrogen has been consumed, the catalyst is removed byfiltration and the filtrate is concentrated at reduced pressure. Thesolid product thus obtained is taken up with isopropyl ether, isfiltered and is dried in the oven to obtain 19.8 g of3-tert-butoxycarbonylaminomethylazetidine. M.p. 112°-114° C.

PREPARATION III

a) 10 g (0.0394 mol) of 1-benzhydryl-3-methylazetidin-3-ol (S.S.Chattergee and A. Shoeb, Synthesis 1973, p. 153-154) are dissolved in100 ml of anhydrous pyridine, the mixture is cooled to -20° C. and 7.3 g(0,063 mol) of methanesulphonyl chloride are added dropwise. Thetemperature is kept below -10° C., stirring is carried out at thistemperature for 1 hour and the reaction mixture is left between 0° C.and 3° C. for two days. It is poured into 600 ml of water/ice, theprecipitate is recovered by filtration and is washed with water. Afterdrying in the oven at 50° C. for 2 hours the product is taken up inisopropyl ether (100 ml), is filtered and is dried in the oven at 50° C.overnight to obtain approximately 10 g of1-benzhydryl-3-methanesulphonyloxy-3-methylazetidine.

b) 3-Acetylaminomethyl-3-methylazetidine hydrochloride is obtained byoperating as described in PREPARATION I, stages a), b), c) and d), butstarting with the compound obtained in stage a) above.

PREPARATION IV

a) A solution of 2.6 g (0.025 mol) of diisopropylamine in 80 ml ofanhydrous tetrahydrofuran is cooled to -78° C. under nitrogen and 10 mlof a 2M solution of n-BuLi in n-hexane are added to it with great care.Stirring is carried out for 30 minutes and a solution of 6.2 g (0.025mol) of 1-benzhydrylazetidine-3-carbonitrile obtained in stage a) ofPREPARATION I in 30 ml of tetrahydrofuran is added to it. After 1 hour'sstirring, a solution of 7.0 g (0.05 mol) of methyl iodide in 10 ml oftetrahydrofuran is added dropwise. Stirring is carried out for 1 hourand the reaction mixture is allowed to warm up to ambient temperature.It is left to stand overnight and the basic solution is neutralized byaddition of approximately 100 ml of a 20% solution of NH₄ Cl and a fewdrops of concentrated HCl. The product is extracted with methylenechloride and the organic phase is concentrated to obtain 6.0 g of1-benzhydryl-3methyl-3-azetidinecarbonitrile which is crystallized fromn-hexane. M.p. 78°-80° C.

b) 4.07 g (0.015 mol) of the compound obtained in stage a) above areadded portionwise to a suspension of 0.85 g (0.0225 mol) of LiAlH₄ in180 ml of ethyl ether while the temperature is controlled. The mixtureis refluxed for 2.5 hours, is cooled in an ice bath and approximately170 ml of water are added to it. It is filtered and the filtrate iswashed with water, is dried over sodium sulphate and is concentrated atreduced pressure to obtain 2.7 g of3-aminomethyl-1-benzhydryl-3-methylazetidine in the form of yellowsemisolid oil. The corresponding addition salt with oxalic acid,crystallized from acetone, has an m.p. of 168°-170° C.

c) A solution of 2.16 g (0.0096 mol) of di-tert-butyl dicarbonate in 15ml of chloroform is added dropwise to a solution of 2.57 g (0.0096 mol)of 3-aminomethyl-1-benzhydryl-3-methylazetidine in 30 ml of anhydrouschloroform under a nitrogen atmosphere. The mixture is stirred atambient temperature under nitrogen overnight and is evaporated todryness to obtain 2.7 g of1-benzhydryl-3-tert-butoxycarbonylaminomethyl-3-methylazetidine. M.p.106°-107° C.

d) A mixture of 4.2 g (0.0115 mol) of the compound obtained in thepreceding stage, 0.5 g of 20% Pd(OH)₂ on carbon, 70 ml of absoluteethanol and 4 ml of ethanol saturated with hydrogen chloride ishydrogenated at atmospheric pressure and 50°-60° C. When the theoreticalquantity of hydrogen has been consumed the product is filtered and thefiltrate is concentrated to dryness. The residue is treated with 10 mlof acetone and is ground wet and filtered to obtain 1.5 g of3-tert-butoxycarbonylaminomethyl-3-methylazetidine. M.p. 189°-191° C.

PREPARATION V

a) 1-Benzyl-3-cyanopyrrolidine

4.8 g (0.004 mol) of methanesulphonyl chloride are added dropwise to asolution of 5 g (0.028 mol) of 1-benzyl-3-pyrrolidinol in 65 ml ofanhydrous pyridine cooled to -20° C. Stirring is carried out for 1 hour,the temperature is allowed to rise to the ambient value and stirring iscontinued for 5 hours. The product is poured onto ice and extracted withmethylene chloride. The organic phase is evaporated in vacuum, producing7.9 g of a crude oil, which is purified by chromatography and elutingwith a 98/2 CH₂ Cl_(2/) MeOH mixture. 4.2 g (0.0166 mol) of the mesylateare obtained and are dissolved in 25 ml of dimethylformamide. A solutionof 3.2 g (0.05 mol) of potassium cyanide in 6 ml of water is added tothe solution thus obtained and is heated to approximately 70° C. for 8hours. After standing overnight, the product is poured onto ice and isextracted with ethyl acetate. The organic phase is washed with water, isdried over Na₂ SO₄ and is concentrated in vacuum producing 2.6 g of anoily product, which is purified by chromatography on a column (eluent:7/3 cyclohexane/ethyl acetate). 1.3 g of the compound referred to in thetitle are obtained. B.p.=100° C./0.3 mmHg.

b) 1-Benzyl-3-aminomethylpyrrolidine

3.49 g (0.019 ml) of the compound obtained in stage a) above are addedto a solution of 1.07 g (0.028 mol) of LiAlH₄ in 140 ml of anhydrousethyl ether, with stirring so as to maintain a constant temperature. Themixture is refluxed for 3 hours, is cooled, and the excess LiAlH₄ isdestroyed by very slow addition of 200 ml of water. After filtering, theorganic phase is separated off. The aqueous phase is extracted withmethylene chloride and this extract is added to the organic phase. Afterdrying over Na₂ SO₄ and evaporating in vacuum, 3.48 g of1-benzyl-3-aminomethylpyrrolidine are obtained.

c) 1-Benzyl-3-(tert-butoxycarbonylaminomethyl)-pyrrolidine

A solution of 3.9 g (0.0179 mol) of di-tert-butyl dicarbonate in 8 ml ofCHCl₃ is added very slowly and with stirring to a solution of 3.4 g(0.0179 mol) of 1-benzyl-3-aminomethylpyrrolidine in 34 ml of anhydrousCHCl₃ under nitrogen atmosphere. The mixture is left stirred undernitrogen overnight at ambient temperature. The solvent is evaporated invacuum and 5.5 g of an oil are obtained, which is purified bychromatography on a column, eluted with a 98/2 CH₂ Cl_(2/) MeOH mixture.Yield: 2.5 g (48%).

d) 3-(tert-Butoxycarbonylaminomethyl)pyrrolidine

2.1 g (0,0072 mol) of the compound obtained in stage c) above aredissolved in 30 ml of absolute ethanol. 0.3 of Pd(OH)₂ on carbon(Pearlman catalyst) are added to it and hydrogenation is carried out at45° C. and atmospheric pressure for 5 hours. The product is filtered andconcentrated in vacuum, producing 1.5 g of3-(tert-butoxycarbonylaminomethyl)pyrrolidine.

PREPARATION VI

a) 1-Benzyl-3-pyrrolidinone oxime hydrochloride.

A solution of 9.7 g (0.139 mol) of hydroxylamine hydrochloride in 30 mlof water is added dropwise to a solution of 25 g (0.19 mol) of1-benzyl-3-pyrrolidinone in 30 ml of ethanol. The materials are left atambient temperature for 30 minutes and are heated to 35° C. for 30minutes and concentrated at reduced pressure at 50° C. The solid productthus obtained is crystallized from isopropyl alcohol. M,p, 103°-108° C.Yield: 64.5%.

b) 1-Benzyl-3-pyrrolidineamine.

A solution of 7.3 g (0.192 mol) of LiAlH₄ in 300 ml of anhydrous ethylether is prepared and 22 g (0.096 mol) of the compound obtained in stagea) above are added to it portionwise at ambient temperature.

The materials are left at ambient temperature for 1 hour and refluxedfor 3.5 hours. The excess LiAlH₄ is destroyed and filtration is carriedout. The filtrate is extracted with 150 ml of a 1N solution ofhydrochloric acid. The solution is made basic (pH 12) and is extractedwith ethyl ether. The organic phase is dried and concentrated to obtain11 g of the product referred to above.

c) 3-Acetylamino-1-benzylpyrrolidine.

A solution of 16 g (0.178 mol) of acetic anhydride in 25 ml of ethylacetate is added dropwise to a solution of 24 g (0.13 mol) of thecompound obtained in the preceding stage in 125 ml of ethyl acetate, andthe mixture is stirred for 30 minutes until the reaction has ended. Themixture is made basic by adding 134 ml of a 2N NaOH solution, theorganic phase is separated off, the aqueous phase is extracted with 50ml of ethyl acetate, the product is dried and concentrated and 150 ml ofcyclohexane are added to it to obtain 11.3 g of3-acetylamino-1-benzylpyrrolidine. M.p. 83°-85° C.

d) 3-Acetylaminopyrrolidine

A mixture of 12.5 g (0.057 mol) of the compound obtained in stage c)above, 1.3 g of 10% Pd/C, 80 ml of 95% ethanol and a drop ofconcentrated hydrochloric acid is hydrogenated at 40° C. When thetheoretical quantity of hydrogen has been consumed, it is filtered andthe filtrate is concentrated to obtain 6.5 g of the title compound inthe form of an oily product.

PREPARATION VII

3-tert-Butoxycarbonylaminopyrrolidine.

The procedure of PREPARATION VI is essentially followed, the aceticanhydride in stage c) being replaced with di-tert-butyl dicarbonate andthe ethyl acetate with chloroform.

PREPARATION VIII

a) 6-Chloro-2-pyridinecarboxylic acid

A mixture of 3.8 g (0.03 mol) of 6-chloro-2-methylpyridine and 10.45 gof KMnO₄ in 380 ml of water is heated to 90° C. for 6 hours. The productis cooled, the pH is adjusted to approximately 4, water is evaporatedoff and the residue is taken up with ethanol. It is filtered and theethanol is evaporated to produce 1.1 g of the compound referred toabove.

b) Ethyl ester of 6-chloro-2-pyridinecarboxylic acid

The compound obtained in stage a) above is heated to reflux for 3 hoursin 10 ml of ethanol saturated with HCl. The ethanol is evaporated off,the residue is taken up with ethyl acetate and is washed with a solutionof sodium bicarbonate and afterwards with water. It is dried over Na₂SO₄ and evaporated in vacuum to obtain 0.7 g of the desired ester.

EXAMPLE 1 2-(3-Aminomethylazetidin-1-yl)-6-chloropyridine hydrochloride

a) A mixture of 6.17 g (0.0375 mol) of the compound obtained inPREPARATION I, 5.54 g (0.0371 mol) of 2,6-dichloropyridine and 13 g(0.094 mol) of anhydrous potassium carbonate in 90 ml of n-amyl alcoholis heated to reflux temperature for 5 hours. It is cooled, filtered, andthe filtrate is concentrated to dryness. The residue is ground wet inwater (50 ml), filtered, and the residue is washed on the filter withwater, taken up in isopropyl ether, evaporated to dryness andcrystallized from 60 ml of ethyl acetate to obtain 6 g of2-(3-acetylaminomethylazetidin-1-yl)-6-chloropyridine. M.p. 136°-138° C.

b) A mixture of 9 g (0.375 mol) of the compound obtained in stage a)above and 35.7 g (0.60 mol) of powdered potassium hydroxide in 36.6 mlof water and 183 ml of 95% ethanol is heated to reflux for 24 h. It isevaporated to a small volume, extracted with ethyl ether, the ether isevaporated off and the residue is dissolved in a mixture of 30 ml ofisopropyl alcohol and 20 ml of ethyl ether. Isopropanol saturated withhydrogen chloride is added to it and the hydrochloride (4.2 g) isrecovered by filtration. M.p. 200°-202° C.

EXAMPLE 2 2-(3-aminomethylazetidin-1-yl)-6-chloropyrazinedihydrochloride

a) A mixture of 2.97 g (0.02 mol) of 2,6-dichloropyrazine, 3.72 g (0.02mol) from the compound from PREPARATION II in free base form and 2.02 g(0.02 mol) of triethylamine in 60 ml of toluene is heated to refluxtemperature for 48 hours. It is filtered hot in vacuum and the solventis evaporated off.

b) The crude product thus obtained (4 g) is reacted at ambienttemperature overnight with 25 ml of a solution of hydrochloric acid inethanol. The precipitate is separated off by filtration and is washedwith ethanol to obtain a yellow solid product (2.7 g) crystallized fromethanol by adding a few drops of water. M.p. 133°-135° C.

EXAMPLE 3 2-(3-Aminomethylazetidin-1-yl)-4-chloropyrimidinedihydrochloride

The compound referred to in the title is obtained essentially byfollowing the procedure described in Example 2 but starting with2,4-dichloropyrimidine instead of 2,6-dichloropyrazine. M.p. >300° C.Yield 76%.

EXAMPLE 4 2-(3-Dimethylaminomethylazetidin-1-yl)-6-chloropyridineoxalate

0.5 g (0.0025 mol) of the compound of Example 1 in free base form aredissolved in 0.5 ml of 85% formic acid (0.013 mol). 0.6 ml of 38%formaldehyde (0.08 mol) are added to it and heated to 100° C. for 1.5hours. The mixture is adjusted to basic pH by adding a solution of NaOH,it is extracted with ethyl acetate, the combined organic extracts aredried over Na₂ SO₄ and are concentrated at reduced pressure to obtain ayellow oil (0.45 g). This oil is dissolved in 3 ml of isopropanol and asolution of 0.25 g of oxalic acid in 1 ml of isopropanol is added to it.The mixture is heated to reflux temperature until dissolved and allowedto cool, to recover 0.4 g of the compound referred to in the title thusprecipitated. M.p. 85°-90° C.

EXAMPLE 5 2-(3-Aminomethylazetidin-1-yl)-6-bromopyridinetrihydrochloride

a) A mixture of 8.9 g (0.04 mol) of3-tert-butoxy-carbonylaminomethylazetidine, 9.47 g (0.04 mol) of2,6-dibromopyridine and 13.8 g (0.1 mol) of anhydrous potassiumcarbonate in 100 ml of dimethylsulphoxide is heated to 110° C. for 3hours. It is poured into water, extracted with ethyl acetate, thecombined organic extracts are washed with water, dried and evaporated todryness to obtain 13 g of a yellow oil, which is purified by flashchromatography on a silica gel column by eluting with 2/8 ethylacetate/cyclohexane. Yield of2-(3-tert-butoxycarbonylaminomethylazetidin-1-yl)-6-bromopyridine: 4.5g. M.p. 138°-141° C. (hexane).

b) 1 g of the latter product (0.029 mol) is treated with 10 ml ofethanol saturated with hydrogen chloride, with stirring at ambienttemperature for 4 hours. It is evaporated in vacuum, taken up inisopropanol and filtered to obtain 0.85 g of the compound referred to inthe title. M.p. 185°-187° C.

EXAMPLE 6 2-(3-Aminomethylazetidin-1-yl)-3-chloropyridine oxalate

a) 2-(3-Acetylaminomethylazetidin-1-yl)-3-chloropyridine is obtained byfollowing the procedure described in stage a) of Example 1, but using2,3-dichloropyridine instead of 2,6-dichloropyridine. M.p. 109°-111° C.

b) A solution of 0.6 g (0.025 mol) of the compound obtained above in 3ml of 6N HCl is heated to reflux for 10 hours. It is evaporated atreduced pressure and the water is removed by adding absolute ethanol andevaporating it off, twice. The residue is taken up with a very smallquantity of water and made basic by adding a solution of NaOH. It isextracted with ethyl acetate, the combined organic extracts are driedover Na₂ SO₄ and evaporated at reduced pressure to obtain 0.6 g of ayellow oil, which is dissolved in 4 ml ol ethanol and acidified byadding a solution of ethanol saturated with oxalic acid. 0.3 g of thecompound referred to in the title are obtained by filtration. M.p.188°-191° C.

EXAMPLE 7 2-(3-Aminomethylazetidin-1-yl)-5-chloropyridine hydrochloride

A mixture of 0.85 g (0.0038 mol) of the compound from PREPARATION II,0.56 g (0.0038 mol) of 2,5-dichloropyridine and 1.3 g (0.0095 mol) ofanhydrous K₂ CO₃ in 10 ml of dimethyl sulphoxide is heated with stirringto 100° C. for 4.5 hours. The mixture is poured into water, extractedtwice with ethyl acetate and concentrated at reduced pressure to obtainan oily product, which is purified by chromatography on a column ofsilica gel by eluting with a 1/1 ethyl acetate/cyclohexane mixture. 0.32g of a semisolid oil are thus obtained, which is dissolved in 3 ml ofethanol saturated with hydrogen chloride. After 3 hours stirring atambient temperature the precipitate is filtered off, washed first withethanol and then with ethyl ether and is dried to obtain 0.2 g of thecompound referred to in the title. M.p. 290°-295° C. (dec.).

EXAMPLE 8 2-(3-Aminomethylazetidin-1-yl)-6-bromopyridine hydrochloride

This compound (the same as that in Example 5) is obtained also bystarting with 3-acetylaminomethyl-azetidine, following the procedure ofExample 1a) and subjecting the2-(3-acetylaminomethylazetidin-1-yl)-6-bromopyridine thus obtained (M.p.115°-117° C.) to an acidic hydrolysis and following essentially theprocedure described in Example 1b).

EXAMPLE 9 2-(3-Aminomethyl-3-methylazetidin-1-yl)-6-chloropyridinemaleate

a) A mixture of 1.36 g (0.0057 mol) of the compound from PREPARATION IV,0.85 g (0.0057 mol) of 2,6-dichloropyridine and 2.0 g (0.014 mol) of K₂CO₃ in 15 ml of n-pentyl alcohol is heated to reflux for 6 hours. It iscooled, the salts are removed by filtration and the material isevaporated at reduced pressure to obtain a yellow oil, which is purifiedby chromatography on a column of silica gel by eluting with a 95/5methylene chloride/methanol mixture. 750 mg of 2-(3-tert-butoxycarbonylaminomethyl-3-methylazetidin-1-yl)-6-chloropyridine arethus obtained. M.p. 108°-111° C.

b) A solution of 0.7 g (0.0022 mol) of the compound obtained in stage a)above in 10 ml of ethanol saturated with hydrogen chloride is stirredovernight. The ethanol is evaporated off, the oily residue is taken upwith a 10% solution of Na₂ CO₃ and is extracted with ethyl acetate.Evaporation at reduced pressure produces 400 mg of a yellow oilyproduct, which is dissolved in a small quantity of ethanol andprecipitated in the form of maleate by adding a solution of maleic acidin ethanol. M.p. 164°-166° C. Yield: 400 mg.

EXAMPLE 10 2-(3-Methylaminomethylazetidin-1-yl)-6-chloropyridine

a) A mixture of 0.56 g (0.0038 mol) of 2,6-dichloro-pyridine, 0.85 g(0.0038 mol) of the compound from PREPARATION II and 1.3 g (0.0095 mol)of ground anhydrous K₂ CO₃ in 10 ml of dimethyl sulphoxide is heated to100° C. for 4.5 hours. It is poured into water and extracted with ethylacetate. The extract is evaporated to dryness and the residue ispurified by chromatography on a column of silica gel by eluting with a7/3 cyclohexane/ethyl acetate mixture. 0.33 g of2-(3-tert-butoxycarbonylaminomethylazetidin-1-yl)-6-chloropyridine areobtained by evaporating the fractions containing it. M.p. 124°-126° C.

b) A solution of 0.31 g (0.001 mol) of the compound obtained in stage a)above in 1 ml of tetrahydrofuran is cooled to a temperature of between0° and 5° C. and 3 ml of a 1M solution of borane-tetrahydrofuran complexare added to it. The mixture is heated to reflux overnight, is cooled, 2ml of ethanol are added to it and the mixture is heated to reflux for 1hour; it is cooled again, 3 ml of a solution of HCl are added and themixture is heated to reflux for 2 hours. The product is evaporated todryness in vacuum, the residue is taken up with absolute ethanol andevaporated to dryness in vacuum. This operation is repeated and then theresidue thus obtained is chromatographed on a column of silica gel byeluting with a 7/3 ethyl acetate/methanol mixture. 0.15 g of thecompound referred to in the title are recovered in the form of a yellowoil.

EXAMPLE 11 2-(3-Methylaminomethylazetidin-1-yl)-6-chloropyridine oxalate

The compound of Example 10 is prepared in the form of oxalate by thefollowing alternative method:

a) A mixture of 1.5 g (0.0076 mol) of2-(3-amino-methylazetidin-1-yl)-6-chloropyridine (the compound ofExample 1 in free base form) and 1.1 g (0.0152 mol) of ethyl formate isheated to 85° C. for 6 hours. It is left to stand overnight and istreated with hexane and separated. The residue is evaporated to dryness,producing a semisolid oil (1.15 g) corresponding to the N-formylderivative.

b) A 1M solution of BH₃ -THF (12 ml) is added very slowly to a solutionof 1.1 g (0.0049 mol) of the compound obtained in stage a) above in 4 mlof anhydrous tetrahydrofuran under a nitrogen atmosphere and cooled to0° C. The mixture is heated to reflux for 4 hours, cooled to 0° C., and6 ml of methanol are added to it very slowly dropwise. The product isheated to reflux for half an hour, is cooled, 5 ml of 5N HCl are addedto it and the mixture is heated again to reflux for 90 minutes. Theorganic solvent is evaporated off, the aqueous phase is washed withethyl acetate and is made basic by adding a concentrated solution ofNaOH. It is extracted with ethyl acetate, the organic extract is washedwith a very small quantity of water, is dried over Na₂ SO₄ and isevaporated in vacuum. The oily product is dissolved in a small quantityof isopropanol and an excess of oxalic acid is added to it. After a fewdays at 2°-4° C. the compound referred to in the title is isolated byfiltration. M.p. 160°-170° C.

EXAMPLE 12 6-[(3-Aminomethyl)azetidin-1-yl]-2-pyridinecarbonitrilehydrochloride

a)6-[(3-tert-Butoxycarbonylaminomethyl)azetidin-1yl]-2-pyridinecarbonitrile

A mixture of 0.2 g (0.00058 mol) of2-bromo-6-(3-tert-butoxycarbonylaminomethyl)azetidin-1-ylpyridineobtained in stage a) of Example 5, 5 ml of anhydrous dioxane, 0.68 g(0.00058 mol) of tetrakis(triphenylphosphine)palladium, 0.22 g (0.0007mol) of tributyltin cyanide, 0.07 g (0.0017 mol) of anhydrous LiCl and afew crystals of 2-tert-butyl-4-methylphenol is heated to reflux for 4hours. It is cooled and 6 ml of pyridine and 20 ml of a 1.1M solution oftetrabutylammonium fluoride in tetrahydrofuran are added to it. Afterone night at ambient temperature it is diluted with ethyl ether and isfiltered on Celite. It is concentrated, and an oily product is obtained,which is purified by chromatography by eluting with a 7/3cyclohexane/ethyl acetate mixture. 0.06 g of the intermediate compoundreferred to above are obtained in the form of fluorescent solid product.

b) 6-[(3-Aminomethyl)azetidin-1-yl]-2-pyridinecarbonitrilehydrochloride.

A mixture of 0.06 g of the compound of stage a) above and 0.3 ml oftrifluoroacetic acid in 3 ml of chloroform is stirred at ambienttemperature overnight. It is washed with a saturated solution of NaHCO₃and is extracted with ethyl acetate. The organic phase is dried oversodium sulphate and is concentrated in vacuum to obtain 0.2 g of thecompound referred to in the title, in oil form. It is dissolved in asmall quantity of isopropanol, acidified by adding isopropanol saturatedwith hydrogen chloride and the precipitate is recovered by filtration toobtain 20 mg of the compound referred to in the title. M.p. 275°-280° C.

EXAMPLE 13 6-(3-Aminomethylazetidin-1-yl)-2-aminopyridine hydrochloride

a) 2-tert-Butoxycarbonylamino-6-chloropyridine.

A solution of 4.36 g (0.02 mol) of di-tert-butyl dicarbonate in 10 ml ofmethylene chloride is added dropwise to a solution of 2.57 g (0.02 mol)of 2-amino-6-chloropyridine in 25 ml of methylene chloride. It is leftat ambient temperature overnight, washed with a 1N solution of HCl andwith water, and is dried over sodium sulphate and concentrated in vacuumto obtain 4.0 g of the compound referred to above, as a yellow oil.

b)6-[(3-tert-Butoxycarbonylaminomethyl)azetidin-1-yl]-2-tert-butoxycarbonylaminopyridine.

A mixture of 1.7 g (0.0075 mol) of the compound obtained in stage a)above, 1.4 g (0.0063 mol) of 3-tert-butoxycarbonylaminomethylazetidine(PREPARATION II) and 2.2 g (0.0157 mol) of K₂ CO₃ in 20 ml of dimethylsulphoxide is heated to 120° C. ext. overnight. 20 ml of water are addedand the mixture is extracted with ethyl acetate. The organic phase iswashed with water and is dried and evaporated in vacuum. The residue ispurified by chromatography by eluting with a 1/9 ethylacetate/cyclohexane mixture to obtain 1 g of the compound referred toabove, which is washed with hexane.

c) 6-(3-Aminomethylazetidin-1-yl)-2-aminopyridine hydrochloride.

A mixture of 0.9 g of the compound from stage b) above and 15 ml ofethanol saturated with hydrogen chloride is stirred at ambienttemperature overnight. It is evaporated to dryness to obtain thecompound referred to in the title, in the form of an oily product whichcrystallizes when treated with 95% ethanol.

EXAMPLE 14 2-(3-Aminomethylazetidin-1-yl)-6-trifluoromethylpyridinehydrochloride

a)2-[(3-tert-Butoxycarbonylaminomethylazetidin-1-yl)-6-trifluoromethylpyridine.

A mixture of 1.55 g (0.007 mol) of3-tert-butoxycarbonylaminomethylazetidine (PREPARATION II), 1.52 g(0.0084 mol) of 2-chloro-6-trifluoromethylpyridine and 2.41 g (0.0175mol) of potassium carbonate in 20 ml of dimethyl sulphoxide is heated to120° C. ext. with stirring overnight. 30 ml of water are added, themixture is extracted with ethyl acetate and the organic phase is washedwith water, dried and evaporated in vacuum. The residue is purified bychromatography by eluting with a 7/3 cyclohexane/ethyl acetate mixtureto obtain 0.95 g of the intermediate compound referred to above, in theform of white solid product.

b) 2-(3-Aminomethylazetidin-1-yl)-6-trifluoromethylpyridinehydrochloride.

A solution of 0.95 g of the compound obtained in the preceding stage in12 ml of ethanol saturated with hydrogen chloride is stirred at ambienttemperature for 3 hours. The ethanol is evaporated off, the oily residuethus obtained is taken up with isopropanol and the product of the titleis crystallized by refrigerating. 0.35 g are obtained. M.p. 149°-151° C.

EXAMPLE 15 2-(3-Aminomethylazetidin-1-yl)-6-methoxypyridinehydrochloride

a) 2-[(3-tert-Butoxycarbonylaminomethylazetidin-1-yl)-6-methoxypyridine.

The procedure of stage a) of Example 16 is followed essentially byemploying 1.2 g of 2- chloro-6-methoxypyridine instead of2-chloro-6-trifluoro-methylpyridine and the intermediate productreferred to above is obtained in the form of oil.

b) 2-(3-Aminomethylazetidin-1-yl)-6-methoxypyridine hydrochloride.

The procedure of stage b) of Example 16 is followed, but starting withthe intermediate compound obtained in stage a) above and the compoundreferred to in the title is obtained. M.p. 160°-165° C.

EXAMPLE 16 2-(3-Aminomethylazetidin-1-yl)-3-chloropyridine hydrochloride

a) 2-[(3-tert-Butoxycarbonylaminomethylazetidin-1-yl)-3-chloropyridine.

A mixture of 0.85 g (0.0038 mol) of the compound from PREPARATION II,0.56 g (0.0038 mol) of 2,3-dichloropyridine and 1.3 g (0.0095 mol) ofpotassium carbonate in 10 ml of dimethyl sulphoxide is heated to 110° C.ext. for 4.5 hours. It is poured into water and extracted with ethylacetate. The organic phase is dried over sodium sulphate, isconcentrated in vacuum, and the residue is purified by chromatography toobtain 0.7 g of the intermediate product referred to above.

b) 2-(3-Aminomethylazetidin-1-yl)-3-chloropyridine hydrochloride.

The product obtained in stage a) is dissolved in 70 ml of ethanolsaturated with hydrogen chloride. It is stirred at ambient temperaturefor 3 hours, the ethanol is evaporated off, the product is taken up witha few millilitres of hot isopropanol and is cooled and filtered toobtain 0.45 g of the compound referred to in the title. M.p. 187°-192°C.

EXAMPLE 17 2-(3-Aminomethylazetidin-1-yl)-6-methylpyridine hydrochloride

a) 2-[(3-tert-Butoxycarbonylaminomethylazetidin-1-yl)-6-methylpyridine.

A mixture of 2.9 g (0.013 mol) of the compound from PREPARATION II, 2.2ml (0.0195 mol) of 2-chloro-6-methylpyridine and 4.5 g (0.0325 mol) ofanhydrous potassium carbonate in 35 ml of dimethyl sulphoxide is heatedto 120° C. for 6 hours. 50 ml of water are added, the mixture isextracted with ethyl acetate, the organic phase is washed with water andis dried over sodium sulphate and evaporated at reduced pressure. Theoily residue is purified by chromatography by eluting with a 7/3cyclohexane/ethyl acetate mixture to obtain 0.46 g of the productreferred to above.

b) 2-(3-Aminomethylazetidin-1-yl)-6-methylpyridine hydrochloride.

0.46 g (0.0016 mol) of the compound obtained in stage a) above aredissolved in 4 ml of ethanol saturated with hydrogen chloride and leftat ambient temperature for 3 hours. A small quantity of isopropanol isadded to it and the material is filtered. The solid product is washedwith ethyl ether and is dried to obtain 350 mg of the compound referredto in the title. M.p. 300°-310° C. (dec.).

EXAMPLE 18 6-[(3-Aminomethyl)azetidin-1-yl]-2-pyridinecarbonitrileoxalate

The compound of Example 10 is prepared in the form of oxalate by thefollowing alternative method:

A mixture of 7.3 g (0.052 mol) of 6-chloro-pyridine-2-carbonitrile (CAS103 : 71164n), 8.31 g (0.052 mol) of 3-aminomethylazetidinedihydrochloride and 25 g of anhydrous K₂ CO₃ in 130 ml of dimethylsulphoxide is heated to 80°-85° C. overnight.

It is filtered, evaporated at reduced pressure at 70°-80° C. and theresidue is purified by chromatography on a column by eluting withmethanol. On evaporating the solvent, 3.8 g of the free base areobtained, which is dissolved in a small quality of acetone andprecipitated in the form of oxalate by adding an excess of oxalic acid.M.p. 185°-190° C.

EXAMPLE 19 Hydrochloride of the ethyl ester of6-(3-aminomethyl-azetidin-1-yl)-2-pyridinecarboxylic acid

a) A mixture of 3.15 g (0.0092 mol) of the compound obtained in stage a)of EXAMPLE 5, 3.7 g (0.00117 mol) of tributylvinyltin, 1.16 g (0.027mol) of anhydrous LiCl, 0.2 g (0.00018 mol) oftetrakis(triphenylphosphine)palladium and a very small quantity of2-tert-butyl-4-methylphenol in 54 ml of anhydrous dioxane is heated toreflux for 3 hours. It is left to cool and 6 ml of pyridine and 15 ml ofa 1.1M solution of tetrabutylammonium chloride in tetrahydrofuran areadded to it. After stirring overnight, 100 ml of ethyl ether are addedand the mixture is filtered on Celite. The organic solution isevaporated to dryness to obtain2-(3-tert-butoxy-carbonylaminomethylazetidin-1-yl)-6-vinylpyridine inthe form of a yellow oil, which is crystallized from hexane (2.4 g).M.p. 85°-87° C.

b) 6.8 g (0.031 mol) of sodium periodate are added to a mixture of 3.1 g(0.01 mol) of the compound obtained above, 0.07 g (0.00028 mol) ofosmium tetraoxide, 80 ml of tetrahydrofuran and 23 ml of water and arestirred at ambient temperature for 3 hours. The product is poured into120 ml of water, extracted with ethyl acetate, the organic phase iswashed with water and is dried over sodium sulphate, is filtered and isevaporated to dryness. A yellow oil (3 g) is obtained which, aftercrystallization on adding a small quantity of ethyl ether, gives 2.2 gof6-(tert-butoxycarbonylaminomethylazetidin-1-yl)-2-pyridinecarboxaldehyde.M.p. 125°-127° C.

c) A solution of 10.3 g of 80% NaClO₂ and 9.2 g of NaH₂ PO₄ in 55 ml ofdistilled water is added to a solution of the compound obtained in stageb) above in 150 ml of tert-butanol and is stirred at ambient temperaturefor 1 hour. 120 ml of water are then added and the mixture is extractedwith ethyl acetate. The organic extract is dried over sodium sulphateand filtered and is evaporated to dryness to obtain a yellow oilcorresponding to6-(3-tert-butoxycarbonylaminomethylazetidin-1-yl)-2-pyridine carboxylicacid, which is purified by chromatography on a column by eluting with a7/3 ethyl acetate/methanol mixture.

d) A mixture of 1.9 g of the compound obtained in stage c) above and 10ml of absolute ethanol saturated with hydrogen chloride is stirred atambient temperature overnight; it is then evaporated to dryness, 15 mlof ethanol saturated with hydrogen chloride are added and the mixture isheated to reflux for 3 hours. It is evaporated to dryness, the residueis taken up with 50 ml of ethyl acetate and 20 ml of an aqueous solutionof sodium bicarbonate, the organic phase is separated off and is thenwashed with water, dried and evaporated. The residue is taken up with 20ml of acetone, the solution is acidified by adding isopropanol saturatedwith hydrogen chloride and the crystallized product is recovered byfiltration. M.p. 118°-120° C.

EXAMPLE 20 Hydrochloride of the ethyl ester of6-(3-aminomethyl-azetidin-1-yl)-2-pyridinecarboxylic acid

The compound of Example 19 is also obtained by the following alternativemethod:

A mixture of 0.65 g (0.0029 mol) of the compound from Preparation II inthe form of hydrochloride, 0.53 g (0.0029 mol) of the compound frompreparation VIII and 1.0 g (0.00725 mol) of anhydrous K₂ CO₃ in 8 ml ofdimethyl sulphoxide is heated to 110° C. with stirring overnight. Thereaction mixture is poured into water and is extracted twice with ethylacetate. The organic phase is concentrated in vacuum and the oilyresidue thus obtained is purified by chromatography by eluting with a7/3 cyclohexane/ethyl acetate mixture. The product thus obtained isdissolved in 3 ml of ethanol saturated with HCl and is left stirred atambient temperature overnight. 30 ml of absolute ethanol are added toit, the mixture is concentrated at reduced pressure and the residue istaken up with isopropanol and the compound of the title is left tocrystallize and is then isolated by filtration. Yield 0.16 g. M.p.119°-121° C.

EXAMPLE 21 6-[(3-Aminomethyl)azetidin-1-yl]-2-pyridinecarboxamide

A mixture of 0.8 g (0.0042 mol) of the compound from Example 10, 4 ml ofdistilled water and 8 ml of 5N HCl is heated to reflux temperature for 4hours and is evaporated to dryness. The residue is taken up with ethanoland the ethanol is evaporated off, this operation is repeated severaltimes and finally the residue is taken up with isopropanol. After onenight at 2°-4° C. the product is filtered, producing 0.95 g of thecompound referred to in the title. M.p. 297°-303° C. A product withm.p. >310° C. is obtained by crystallization from ethanol at 90° C.

EXAMPLE 22 6-(3-Aminomethylazetidin-1-yl)-2-vinylpyridine hydrochloride

0.5 g (0.0017 mol) of the compound obtained in stage a) of Example 19are dissolved in 5 ml of ethanol saturated with hydrogen chloride andare stirred at ambient temperature for 3 hours. The ethanol isevaporated off, the residue is taken up in isopropanol and is filteredto obtain 0.35 g of the compound referred to in the title, in the formof yellow solid. M.p. 285°-286° C.

EXAMPLE 23 6-(3-Aminomethylazetidin-1-yl)-2-pyridinecarboxaldehydehydrochloride

0.6 g (0.002 mol) of the compound obtained in stage b) of Example 19 aredissolved in 8 ml of ethanol saturated with hydrogen chloride and arestirred at ambient temperature for 3 hours. The material is concentratedin vacuum and the product referred to in the title is obtained in theform of a dark oil.

EXAMPLE 24 2-[(3-Aminomethyl)azetidin-1-yl]-6-(1piperidinyl)pyridinehydrochloride 6-(1-piperidinyl)pyridine

A mixture of 0.3 mg (0.8 mmol) of the compound obtained in stage a) ofExample 5, 0.1 ml (0.8 mmol) of piperidine and 0.17 g (1.2 mmol) of K₂CO₃ in 3 ml of dimethyl sulphoxide is heated to approximately 100° C.with stirring for 8 hours. The reaction mixture is poured into water andis extracted twice with ethyl acetate and once with methylene chloride.It is concentrated at reduced pressure and 0.4 g of an oily product isobtained, which crystallizes spontaneously.

b) 2-[(3-Aminomethyl)azetidin-1-yl]-6-(1-piperidinyl)pyridinehydrochloride

The product obtained in stage a) is dissolved in 3 ml of ethanolsaturated with HCl, is left stirring at ambient temperature overnight,and the product referred to in the title is isolated by filtration.

EXAMPLE 25 2-(3-Aminopyrrolidin-1-yl)-6-chloropyrazine dihydrochloride

a) 2-Chloro-6-(3-tert-butoxycarbonylaminopyrrolidin- 1-yl)pyrazine.

A mixture of 2.24 (0.012 mol) of the compound obtained in PREPARATIONVII, 1.79 g (0.012 mol) of 2,6-dichloropyrazine and 1.2 g (0.012 mol) oftriethylamine in 50 ml of toluene is heated to reflux for 24 hours. Itis filtered hot to remove the salts, the solvent is evaporated off andthe oily product which is obtained is purified by chromatography on acolumn of silica gel by eluting with a 9/1 methylene chloride/ethylacetate mixture. 600 mg of the compound referred to above are thusobtained.

b) 6-(3-Aminopyrrolidin-1-yl)-2-chloropyrazine dihydrochloride.

The product from stage a) above is dissolved in 10 ml of ethanolsaturated with hydrogen chloride and is left stirred at ambienttemperature overnight. It is filtered and 0.41 g of the title compoundare obtained in the form of a yellow solid product which isrecrystallized from ethanol. M.p. 233°-235° C.

EXAMPLE 26 2-(3-Aminopyrrolidin-1-yl)-6-chloropyrimidine dihydrochloride

a) 6-Chloro-2-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)pyrimidine.

A mixture of 2.77 g (0.015 mol) of 3-tert-butoxycarbonylaminopyrrolidine(PREPARATION VII), 2.21 g (0.015 mol) of 2,6-dichloropyrimidine and 1.5g (0.013 mol) of triethylamine in 50 ml of toluene is heated to refluxfor 48 hours. It is allowed to cool, filtered and the filtrate isevaporated to dryness to obtain a crude product, which is purified bychromatography on a column of silica gel by eluting with a 98/2methylene chloride/methanol mixture. 800 mg of the compound referred toabove are obtained. M.p. 97°-98° C.

b) 2-(3-Aminopyrrolidin-1-yl)-6-chloropyrimidine dihydrochloride.

The compound obtained in stage a) above is dissolved in 10 ml of ethanolsaturated with hydrogen chloride and is stirred at ambient temperatureovernight. The precipitate is filtered off and is then crystallized fromabsolute ethanol to obtain 0.56 g of the compound referred to in thetitle. M.p. >330° C.

EXAMPLE 27 2-(3-Aminopyrrolidin-1-yl)-6-chloropyridine hydrochloride

a) 2-(3-Acetylaminopyrrolidin-1-yl)-6-chloropyridine.

A mixture of 4.8 g (0.0375 mol) of the compound obtained in PREPARATIONVI, 5.54 g (0.0371 mol) of 2,6-dichloropyridine and 6.5 g (0.047 mol) ofanhydrous potassium carbonate in 90 ml of n-amyl alcohol is heated toreflux for 5 hours. It is cooled, filtered and the filtrate isconcentrated to dryness. The residue is ground wet in water (50 ml), isfiltered, the residue is washed on the filter with water, is taken up inisopropyl ether, the solution is evaporated to dryness and the productis crystallized from 60 ml of ethyl acetate to obtain 5.7 g of thecompound referred to above.

b) 2-(3-Aminopyrrolidin-1-yl)-6-chloropyridine hydrochloride.

A mixture of 4.46 g (0.187 mol) of the compound obtained in stage a)above and 17.8 g (0.30 mol) of powdered potassium hydroxide in 18.3 mlof water and 90 ml of 95% ethanol is heated to reflux for 24 hours. Itis evaporated to a small volume, extracted with ethyl ether, the etheris evaporated off and the residue is dissolved in a mixture of 15 ml ofisopropyl alcohol and 10 ml of ethyl ether. Isopropanol saturated withhydrogen chloride is added to it and the hydrochloride (2.3 g) isrecovered by filtration. M.p. 258°-260° C.

EXAMPLES 28-33

By essentially following the procedure of Example 25, but replacing2,6-dichloropyrazine with 2,6-dibromopyridine, 2,3-dichloropyridine,2,5-dichloropyridine, 2-chloro-6-trifluoromethylpyridine,2-chloro-6-methoxypyridine and 2-chloro-6-methylpyridine the followingare obtained, respectively:

2-(3-aminopyrrolidin-1-yl)-6-bromopyridine (Ex. 28),

2-(3-aminopyrrolidin-1-yl)-3-chloropyridine (Ex. 29),

2-(3-aminopyrrolidin-1-yl)-5-chloropyridine (Ex. 30),

2-(3-aminopyrrolidin-1-yl)-6-trifluoromethylpyridine (Ex. 31),

2-(3-aminopyrrolidin-1-yl)-6-methoxypyridine (Ex. 32),

2-(3-aminopyrrolidin-1-yl)-6-methylpyridine (Ex. 33),

in the form of addition salts with hydrochloric acid.

EXAMPLE 34 2-(3-Amino-3-methylpyrrolidin-1-yl)-6-chloropyridinehydrochloride

2-(3-Amino-3-methylpyrrolidin-1-yl)-6-chloropyridine hydrochloride isobtained by following the procedure of Example 27 but employing3-acetylamino-3-methylpyrrolidine described in EP-132845 ("ReferenceExample 7") instead of the compound from the PREPARATION VI, in stagea).

EXAMPLE 35 2-(3-Dimethylaminopyrrolidin-1-yl)-6-chloropyridine oxalate

0.25 g (0.00127 mol) of the compound from Example 27 in free base formare dissolved in 0.25 ml of 85% formic acid (0.00564 mol). 0.3 ml of 38%formaldehyde (0.04 mol) are added to it and the mixture is heated to100° C. for 2 hours. It is made basic with the aid of a solution of NaOHand is extracted with ethyl acetate. The organic extracts are dried andthe solvent is evaporated off in vacuum. The residue is dissolved in asmall quantity of isopropanol and a solution of oxalic acid inisopropanol is added to it when hot. The mixture is allowed to cool andthe product referred to in the title is recovered by filtration.

EXAMPLE 36 2-(3-Aminopyrrolidin-1-yl)-6-vinylpyridine hydrochloride

a) 2-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-6-vinylpyridine.

The compound referred to above is obtained essentially by following theprocedure described in stage a) of Example 19 but starting with2-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-6bromopyridine, obtainedby reaction of 2,6dibromopyridine with the compound from PREPARATIONVII, instead of2-(3-tert-butoxycarbonylaminomethylazetidin-1-yl)-6-bromopyridine.

b) 2-(3-Aminopyrrolidin-1-yl)-6-vinylpyridine hydrochloride

The compound referred to in the title is obtained from the compoundobtained in stage a) above and by following the procedure of Example 22.

EXAMPLE 37 Hydrochloride of the ethyl ester of6-(3-aminopyrrolidin-1-yl)-2-pyridinecarboxylic acid

The compound referred to above is obtained by following the procedure ofExample 20 but replacing the compound from PREPARATION II with3-tert-butoxycarbonylaminopyrrolidine.

EXAMPLE 38 6-(3-Aminopyrrolidin-1-yl)-2-pyridinecarbonitrile oxalate

The compound referred to in the title is obtained essentially byfollowing the procedure of Example 20 but replacing3-aminomethylazetidine dihydrochloride with 3-aminopyrrolidinedihydrochloride obtained from the compound from PREPARATION VI byhydrolysis.

EXAMPLE 39 2-[(3-Aminomethyl)pyrrolidin-1-yl]-6-chloropyridinehydrochloride

A mixture of 1.5 g (0.0075 mol) of the compound from PREPARATION V, 1.12g (0.0075 mol) of 2,6-dichloropyridine and 2.5 g (0.0184 mol) of K₂ CO₃in 15 ml of n-amyl alcohol is heated to reflux temperature for 6 hours.It is cooled, the salts are filtered off and the solvent is evaporatedoff in vacuum. An oily product is obtained, which is purified bychromatography on a column by eluting with an 8/2 CH₂ Cl_(2/) ethylacetate mixture. The residue is dissolved in ethanol saturated with HCland after stirring overnight at ambient temperature the precipitate isfiltered off and crystallized from a 30/1 EtOH/H₂ O mixture. M.p. 219°C.

We claim:
 1. 1-Heteroarylazetidine or -pyrrolidine of formula (I)##STR12## in which A denotes a, --CH═N-- or --N═CH-- group;R denotes ahydrogen atom, a halogen atom, a C₁ -C₄ alkyl, C₁ -C₄ alkoxy or C₁ -C₄alkylthio group, a cyano, carboxamido, trifluoromethyl, vinyl or formylgroup, a carboxyl group in free, salt or esterified form, a hydroxyl,hydroxymethyl or mercapto group or an amino, mono- or di(C₁ -C₄alkyl)amino, aminomethyl, mono- or di(C₁ -C₄ alkyl)aminomethyl,1-piperidino, 1-pyrrolidino, 1-piperazino or 4-(C₁ -C₄alkyl)-1-piperazino group, it being possible for this group R to replaceany one of the hydrogen atoms of the heteroaryl nucleus; R₁ is ahydrogen atom or a methyl group; R₂ and R3, which are identical ordifferent, denote a hydrogen atom or a C₁ -C₄ alkyl group; n is 1 or 2,m is 0 or 1 and m+n≧2 and its addition salts with inorganic or organicacids.
 2. 1-Heteroarylazetidine according to claim 1, where n=m=1 offormula (Ia) ##STR13## and its addition salts with acids. 3.1-Heteroarylpyrrolidine according to claim 1 where n=2 of formula (Ib)##STR14## and its addition salts with acids.
 4. 1-Heteroarylazetidine ofclaim 2, where A denotes a --N═CH-- group, and R₁ is hydrogen, and itsaddition salts with acids.
 5. 1-Heteroarylazetidine of claim 4, where Rdenotes a hydrogen or halogen atom, a C₁ -C₄ alkyl, C₁ C₄ alkoxy, cyano,carboxamido, trifluoromethyl, vinyl, formyl, carboxyl in free, salt oresterified form, or amino group and its addition salts with acids. 6.1-Heteroarylpyrrolidine of claim 3, where A denotes a --N═CH-- group, R₁is a hydrogen atom and its addition salts with acids. 7.1-Heteroarylpyrrolidine of claim 7, where R denotes a hydrogen atom, ahalogen atom, a C₁ -C₄ alkyl, C₁ -C₄ alkoxy, cyano, carboxamido,trifluoromethyl, vinyl, formyl, carboxyl in free, salt or esterifiedform or amino group and its addition salts with acids.
 8. Apharmaceutical composition comprising as active principle at least one1-heteroarylazetidine, 1-heteroarylpyrrolidine or addition salts thereofwith pharmaceutically acceptable acids, as claimed in claim 1, incombination with a pharmaceutically acceptable carrier.
 9. Apharmaceutical composition comprising as active principle at least one1-heteroarylazetidine or acid addition salts thereof, as claimed inclaim 2, in combination with a pharmaceutically acceptable carrier. 10.A pharmaceutical composition comprising as active principle at least one1-heteroarylpyrrolidine or acid addition salts thereof, as claimed inclaim 3, in combination with a pharmaceutically acceptable carrier. 11.A pharmaceutical composition comprising as active principle at least one1-heteroarylpyrrolidine or acid addition salts thereof, as claimed inclaim 4, in combination with a pharmaceutically acceptable carrier. 12.A pharmaceutical composition comprising as active principle at least one1-heteroarylpyrrolidine or acid addition salts thereof, as claimed inclaim 5, in combination with a pharmaceutically acceptable carrier. 13.A pharmaceutical composition comprising as active principle at least one1-heteroarylpyrrolidine or acid addition salts thereof, as claimed inclaim 6, in combination with a pharmaceutically acceptable carrier. 14.A pharmaceutical composition comprising as active principle at least one1-heteroarylpyrrolidine or acid addition salts thereof, as claimed inclaim 7, in combination with a pharmaceutically acceptable carrier. 15.A method for the treatment or prophylaxis of disorders which involve theperipheral or the central serotoninergic system when it is desired tohave a selective agonist action mediated by serotonin 5-HT₃ receptors,which comprises administering to a subject an effective amount of a1-heteroarylazetidine or 1-heteroarylpyrrolidine, or acid addition saltsthereof, as claimed in claim
 1. 16. A method for the treatment orprophylaxis of disorders which involve the peripheral or the centralserotoninergic system when it is desired to have a selective agonistaction mediated by serotonin 5-HT₃ receptors, which comprisesadministering to a subject an effective amount of a1-heteroarylazetidine or acid addition salts thereof, as claimed inclaim
 2. 17. A method for the treatment or prophylaxis of disorderswhich involve the peripheral or the central serotoninergic system whenit is desired to have a selective agonist action mediated by serotonin5-HT₃ receptors, which comprises administering to a subject an effectiveamount of a 1-heteroarylpyrrolidine or acid addition salts thereof, asclaimed in claim
 3. 18. A method for the treatment or prophylaxis ofdysthymic disorders, of psychotic disorders, of cases of anxiety, or ofconstipation, which comprises administering to a subject an effectiveamount of a 1-heteroarylazetidine or 1-heteroarylpyrrolidine, or acidaddition salts thereof, as claimed in claim
 1. 19. A method for thetreatment or prophylaxis of dysthymic disorders, of psychotic disorders,of cases of anxiety, or of constipation, which comprises administeringto a subject an effective amount of a 1-heteroarylazetidine or acidaddition salts thereof, as claimed in claim
 2. 20. A method for thetreatment or prophylaxis of dysthymic disorders, of psychotic disorders,of cases of anxiety, or of constipation, which comprises administeringto a subject an effective amount of a 1-heteroarylpyrrolidine or acidaddition salts thereof, as claimed in claim 3.